Cellular death and necrosis: Chemical, physical and morphologic changes in rat liver

Majno, Guido; M, La Gattuta; Te, Thompson

doi:10.1007/bf00955327

Cited by 143 publications

(45 citation statements)

References 73 publications

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“…Similar reversibility of cell death before 2-2.5 h was found in an in vivo study on ischaemic cell death and subsequent necrosis which employed peritoneally implanted fragments of liver in rats. 37 We identified upregulation of COX-2 expression, a process associated with inflammation, as the most distinct molecular mechanism triggered by the dying fibroblasts. Activity of COX-2 leads to the production of prostanoids, key modulators of the inflammatory cascade.…”

Section: Discussionmentioning

confidence: 91%

Cell–cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression

et al. 2003

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Necrosis was induced by cell-cell contacts of human dermal fibroblasts in three-dimensional culture. Dramatic induction of cyclooxygenase-2 (COX-2) expression was found throughout these necrotizing cell clusters, whereas no increase in expression of apoptosis markers was seen. The cells were rapidly committed to necrosis, and the process could not be reversed by allowing them to spread and adhere on a solid substrate. Induction of COX-2 expression was accompanied by greatly enhanced production of the prostaglandins E 2 , I 2 , and F 2a . When applied exogenously on necrotizing clusters, these prostaglandins delayed cell clustering and further enhanced COX-2 expression. Abolishing prostaglandin production by NS-398 or indomethacin reduced cell membrane damage (as measured by lactate dehydrogenase release into the culture medium). We also identified aenolase-mediated plasminogen activation as the major extracellular proteolytic executor of necrotic cell death. In contrast to inhibition of COX-2, inhibition of plasminogen activation failed to inhibit membrane damage associated with necrosis. Intracellular proteolysis, by caspases, was shown to take part in COX-2 induction. Taken together, our results indicate that cell-cell contacts induce an actively programmed necrotic process that functionally involves COX-2, a known hallmark of inflammation and cancer.

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Section: Discussionmentioning

confidence: 91%

Cell–cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression

et al. 2003

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“…When cells die in vivo, the innate immune system not only alerts the adaptive immune system to potential danger, but also induces an inflammatory response 34 . In this process mediators are generated that act on the local vasculature in ways that cause arterioles to dilate and venules to leak fluid and recruit leukocytes from the blood into the tissue (Fig.…”

Section: Cell Death Damps and Inflammationmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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When a cell dies in vivo the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes, that is, it is part of normal physiological processes, then there is little threat to the organism. In this situation, little else is done other than removing the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized. The importance of this process to host defence and disease pathogenesis has only been appreciated relatively recently. This article will review our current knowledge of these processes.The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection upon repeat exposure to a pathogen. Through subsequent studies by Von Behring and others it rapidly became apparent that the immune system had the potential to respond not only to whole microorganisms, but to virtually any molecule that was "foreign" to the host. However, whereas injection of such molecules would often provoke a robust immune response, this did not invariably occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants [G]) that could boost immune responses to co-administered antigens. Adjuvants were typically of microbial origin and became widely used to promote the effectiveness of immunizations. In the 1960s, Dresser showed that a foreign protein when highly purified would only elicit an immune response if it was admixed with a microbial adjuvant 1 . Injected by itself, the antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used because they were part of standard operating procedures.In 1989 Janeway put these empirical observations into a conceptual framework 3 (Fig. 1). He proposed that the immune system did not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea here was that the immune system evolved to protect organisms against microorganisms and this discrimination between infectious versus noninfectious antigens focused defences on real threats rather than innocuous situations.At this time, it was already recognized that in order to stimulate T cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen presenting cell (APC). Moreover, it was further known that APCs also provided additional costimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (Fig. 1). He postulated that the discrimination between infectious and noninfectious non-self molecules was made by the APCs of the innate immune system through receptors that would recognize pathogen-associated molecular patterns (PAMP...

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“…If the cells are ischemic, oncotic swelling of most cellular compartments contributes to the irreversible destruction of the organelles and the cells (oncosis). The resulting (cell) corpses are then removed by macrophages and usually trigger an exudative inflammatory reaction (Majno et al, 1960;Wyllie et al, 1981;Fawthrop et al, 1991;Majno and Joris, 1995).…”

Section: Cytotoxicity Of Vc:vk 3 Combinationmentioning

confidence: 99%

Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment

Gilloteaux¹,

Jamison²,

Arnold³

et al. 2005

Anat. Rec.

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Feulgen and actin-phalloidin staining as well as gel electrophoresis have been employed in conjunction with cell ultrastructure to describe the effects of 1-, 2-, and 4-hr ascorbate (VC), menadione (VK 3 ), and ascorbate:menadione (VC:VK 3 ) treatments on the T24 human bladder carcinoma cell line. T24 cells exposed to VC alone display blebs and other superficial membrane defects related to membrane alterations and to superficial cytoskeleton changes. VK 3 treatment damages the cell nucleus and organelles, leads to the redistribution of the organelles in the perikaryon as a consequence of cytoskeletal damage, and results in cytoplasmic self-excisions. After VC:VK 3 treatment, the cells show exaggerated alterations characteristic of each vitamin treatment alone, including damaged mitochondria, self-excision of organelle-free pieces of cytoplasm, and extrusion of the perikaryon containing a nucleus surrounded by the damaged organelles. The nuclear envelope appears intact and contains chromatin that decondenses and dissipates. During the cellular demise that concludes with apparent karyolysis, the cells significantly decrease their size and alter their shape. However, the cisterns of rough endoplasmic reticulum are undamaged, but may become dilated. Since the cellular phenomena leading to cell death differ morphologically from apoptosis and necrosis, but entail selfcutting without nuclear bodies, this new form of cell death was called autoschizis. In addition, gel electrophoresis and Feulgen staining demonstrate that autoschizis is accompanied by random DNA degeneration.

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Cellular death and necrosis: Chemical, physical and morphologic changes in rat liver

Cited by 143 publications

References 73 publications

Cell–cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression

Cell–cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression

How dying cells alert the immune system to danger

Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment

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